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Retinoic acid inhibits human melanoma tumor cell invasion
W R Wood1, E A Seftor, D Lotan
1Department of Anatomy, College of Medicine, University of Arizona, Tucson 85724.
Abstract:
The anticancer effects of retinoids have been recognized both in vivo and in vitro; however, little is known about their mechanism of action. Our study evaluated the effects of retinoic acid on the invasiveness of four human melanoma cell lines in vitro and showed a time-dependent inhibition of the ability of these cells to penetrate matrigel-coated filters. The possible mechanisms of action responsible for the anti-invasive effect were further investigated, and the data showed that retinoic acid-treated cells: (a) secreted lower levels of collagenolytic enzymes detected in type IV collagen-containing polyacrylamide gels compared with control cells, which was demonstrated by a decreased ability to degrade [3H]proline-labeled type IV collagen substrate; (b) showed a reduction in PA activity, primarily in the form of tPA, as demonstrated by chromogenic analysis; (c) showed a heterogeneous response with regard to c-myc, c-fos and c-jun mRNA expression, as determined by Northern blot analysis; and (d) demonstrated a decrease in B-actin levels and an increase in vimentin, as demonstrated by Northern blot analysis and SDS-PAGE transblot analysis. Collectively, these data suggest that RA causes an inhibitory effect on tumor cell invasion through a reconstituted basement basement membrane matrix by suppressing type IV collagenolytic activity and PA activity, which is probably triggered through a complex series of oncogene trans-acting factors, ultimately affecting cytoskeletal expression.
Insights
Retinoic acid inhibits melanoma cell invasion by reducing collagenase and plasminogen activator activity. This anticancer effect involves changes in oncogene expression and the cytoskeleton.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Retinoids exhibit anticancer properties, but their precise mechanisms of action remain largely unelucidated.
- Melanoma cell invasion is a critical factor in metastasis and patient prognosis.
Purpose of the Study:
- To investigate the anti-invasive effects of retinoic acid (RA) on human melanoma cells in vitro.
- To elucidate the molecular mechanisms underlying RA's inhibition of melanoma cell invasion.
Main Methods:
- In vitro invasion assays using matrigel-coated filters.
- Analysis of collagenolytic enzyme activity and plasminogen activator (PA) activity.
- Gene expression analysis of oncogenes (c-myc, c-fos, c-jun) and cytoskeletal proteins (beta-actin, vimentin) via Northern blot and SDS-PAGE.
Main Results:
- Retinoic acid significantly inhibited melanoma cell invasion in a time-dependent manner.
- RA treatment reduced the secretion and activity of collagenolytic enzymes and decreased PA activity (primarily tPA).
- Observed heterogeneous changes in c-myc, c-fos, and c-jun mRNA levels, alongside decreased beta-actin and increased vimentin expression.
Conclusions:
- Retinoic acid suppresses melanoma cell invasion by inhibiting type IV collagenolytic and PA activities.
- These effects are likely mediated by complex interactions involving oncogenic factors and alterations in cytoskeletal protein expression.